Hemorrhaging is also the first step in the injury cascade, for example, in the central nervous system (CNS). In both spinal cord and traumatic brain injuries, the first observable phenomena, regardless of mechanism of insult, is hemorrhaging. If one can stop the bleeding, presumably one can preserve tissue and improve outcomes. The primary mechanical insult is very often a small part of the injury. The secondary injury processes that occur over hours, days, and weeks following injury lead to progression and the poor functional outcomes. Stopping those secondary injury processes would mean preservation of greater amounts of tissue. Preservation of tissue means better functional outcomes.
Following injury, hemostasis is established through a series of coagulatory events. The critical steps in terms of platelets involve their activation, binding, and release of a host of growth factors and other molecules including fibrinogen. During vascular injury, collagen is exposed which triggers the activation of platelets. Platelet morphology shifts from a discoid to stellate, and they adhere to the exposed collagen. Once platelet aggregation begins, several inflammatory agents are released from their storage granules including adenosine diphosphate (ADP), which causes the surfaces of nearby circulating platelets to become adherent. Serotonin, epinephrine, and thromboxane A 2 further induce extreme vasoconstriction. The ultimate step, clot formation, is the conversion of fibrinogen, a large, soluble plasma protein produced by the liver and normally present in the plasma, into fibrin, an insoluble, threadlike molecule.
In severe injuries, these endogenous processes fall short and uncontrolled bleeding results. There have been a number approaches to augment these processes and induce hemostasis beyond the external methods. Platelet substitutes which either replace or augment the existing platelets have been pursued for a number of years (Blajchman, J. Thromb. Haemost. 1: 1637-41 (2003)). Administration of allogeneic platelets can help to halt bleeding; however, platelets have a short shelf life, and administration of allogeneic platelets can cause graft versus host disease, alloimmunization, and transfusion-associated lung injuries (Blajchman, J. Thromb. Haemost 1: 1637-41 (2003)). Non-platelet alternatives including red blood cells modified with the Arg-Gly-Asp (RGD) sequence, fibrinogen-coated microcapsules based on albumin, and liposomal systems have been studied as coagulants (Siller-Matula et al., Thromb. Haemost 100: 397-404 (2008)), but toxicity, thrombosis, and limited efficacy are major issues in the clinical application of these products (Frink et al. J. Biomed. Biotech. 2011: 979383 (2011)).
There are a number of approaches to augment hemostasis in the field and clinic including pressure dressings, absorbent materials such as QuikClot®, and intravenous (W) infusion of activated recombinant factor VII (rFVIIa), but the former two are only applicable to exposed wounds, and rFVIIa has had both mixed results, requires refrigeration, and is expensive making it challenging to administer in the field or at the site of trauma. Clearly, a new approach to halt bleeding that is amenable to administration in the field is needed.
Spray on hemostatic systems have many advantages such as quick and even distribution over a broad coverage area. Spray on hemostatic systems can be easily applied to areas that are difficult to contact by swabs or bandages. There is a need for development of spray on systems hemostatic systems.
For a hemostat to be effective for complex trauma, the system needs to be non-toxic, stable when stored at room temperature (i.e. a medic's bag), have the potential for immediate. administration, and possess injury site-specific aggregation properties so as to avoid non-specific thrombosis. For this system to be clinically translatable, ideally it needs to be made with materials previously approved by the FDA. Practically, it also needs to be affordable.